Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Abstract

Abstract-Voltage-gated K ϩ channels (K V ) and thromboxane A 2 (TXA 2 ) play critical roles in controlling pulmonary arterial tone under physiological and pathological conditions. We hypothesized that TXA 2 might inhibit K V channels, thereby establishing a link between these two major pathogenic pathways in pulmonary hypertension. The TXA 2 analogue U46619 inhibited I K(V) (E max ϭ56.1Ϯ3.9%, EC 50 ϭ0.054Ϯ0.019 mol/L) and depolarized pulmonary artery smooth muscle cells via activation of TP receptors. In isolated pulmonary arteries, U46619 simultaneously increased intracellular Ca 2ϩ concentration and contractile force, and these effects were inhibited by nifedipine or KCl (60 mmol/L). U46619-induced contractions were not altered by the inhibitors of tyrosine kinase genistein or Rho kinase Y-27632 but were prevented by the nonselective protein kinase C (PKC) inhibitors staurosporine and calphostin C. Furthermore, these responses were sensitive to Gö-6983 but insensitive to bisindolylmaleimide I and Gö-6976. Based on the specificity of these drugs, we suggested a role for an atypical PKC in U46619-induced effects. Thus, treatment with a PKC pseudosubstrate inhibitor markedly prevented the vasoconstriction, the inhibition of I K(V) , and the depolarization induced by U46619. Western blots showed a transient translocation of PKC from the cytosolic to the particulate fraction on stimulation with U46619. These results indicate that TXA 2 inhibits I K(V) , leading to depolarization, activation of L-type Ca 2ϩ channels, and vasoconstriction of rat pulmonary arteries. We propose PKC as a link between TP receptor activation and K V channel inhibition.

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

“…Inhibition of thromboxane synthase by furegrelate sodium attenuates the development of HPH in neonatal piglet (22). Additionally, thromboxane A 2 inhibits K V channels (along with other K ϩ channels), which causes membrane depolarization and opens VDCC, resulting in pulmonary vasoconstriction (10). The thromboxane A 2 -mediated membrane depolarization is also associated with its activating effect on nonselective cation channels (60).…”

Protein kinase C activation increases endothelial nitric oxide release in mesenteric arteries from orchidectomized rats

“…We observed that this inhibitor also decreased basal-and ACh-induced NO in arteries from orchidectomized rats, indicating the involvement of the conventional PKC isoforms in endothelial NO regulation. Since the atypical PKCz isoform has been reported to modulate vascular responses (Damron et al 1998, De Witt et al 2001, Cogolludo et al 2003 and neuronal NO release (Blanco-Rivero et al 2005a,b), we also tested the possible involvement of this isoform in endothelial NO release. The fact that PKCz-PI decreased the basal-and ACh-induced NO release showed the participation of this isoform.…”

Male Castration Increases Neuronal Nitric Oxide Synthase Activity in the Rat Mesenteric Artery through Protein Kinase C Activation

“…Since the atypical PKC ζ isoform has been described in vascular smooth muscle as modulating vascular responses to different agents [40,41,42], we tested the possible involvement of this isoform in nNOS activity by examining the effect of PKCζ-PI. We found that PKCζ-PI decreased EFS-induced NO release to a similar extent in arteries from control and orchidectomized animals.…”